Abstract 18766: Low-Density-Lipoprotein-Cholesterol and Risk of Diabetes: A Mendelian Randomization Study
Introduction: Low levels of low-density-lipoprotein (LDL)-cholesterol due to statin treatment has been associated with increased risk of type 2 diabetes.
Hypothesis: We tested the hypothesis that low LDL-cholesterol due to genetic variants in the HMGCR, PCSK9, NPC1L1, ABCG8, APOE genes, and variants combined are associated with high risk of type 2 diabetes in the general population.
Methods: We examined associations of plasma LDL-cholesterol levels with observational risk of type 2 diabetes; genetic variants with plasma LDL-cholesterol levels; and genetic variants with risk of type 2 diabetes as an indication of causality using a Mendelian randomization design in 110,217 participants from the Copenhagen General Population Study and the Copenhagen City Heart Study.
Results: In observational analyses, risk of type 2 diabetes was 702% (95% confidence interval: 620%-793%) higher in participants with an LDL-cholesterol <1.5mmol/L versus ≥3.0mmol/L. HMGCR, PCSK9, NPC1L1, ABCG8, and APOE genotypes combined were associated with a 23% lower LDL-cholesterol level. In causal genetic analyses, a 1mmol/L lower LDL-cholesterol was associated with a 0.74kg higher weight, a 0.29kg/m2 higher body mass index, and a nonsignificant odds ratio for type 2 diabetes of 1.08 (95%CI: 0.87-1.35). In causal genetic analysis using obesity associated genetic variants FTO, MC4R, TMEM18, BDNF, and GNPDA2, a 0.29kg/m2 higher body mass index translated into a 3.7% (0.2%-7.2%) higher risk of type 2 diabetes.
Conclusions: Using 110,217 individuals from the general population, we found that low LDL-cholesterol level was observationally associated with high risk of type 2 diabetes. Genetically low LDL-cholesterol was causally associated with high weight and body mass index, and through this effect possibly with high risk of type 2 diabetes.
Author Disclosures: M. Benn: None. S. Stender: None. B.K. Lauridsen: None. A. Tybjaerg-Hansen: None. B.G. Nordestgaard: None.
- © 2016 by American Heart Association, Inc.